Appetite controlled by brain enzyme, researchers find

Scientists have discovered a new kind of nerve cell that appears to tell mice when it is time to stop eating. They hope that the findings, published in the journal Science, could shed new light on how the brain controls food intake and pave the way for new strategies to reduce obesity.

Enjoy the buffet, but let your brain tell you when to stop.

Richard Huganir, PhD, director of the Department of Neuroscience at the Johns Hopkins University School of Medicine, and colleagues were looking at how proteins increase the strength or weakness of the synapses that link brain cells. Synapse strength affects learning and memory, especially in the hippocampus and cortex of the brain.

They were focusing on the role of the enzyme OGT, which among other functions, is involved in the processing of insulin and sugar.

In 1984, Gerald Hart, PhD, director of the Johns Hopkins University School of Medicine's Department of Biological Chemistry and co-leader of the current study, discovered that OGT adds a glucose derivative - called N-acetylglucosamine (GlcNAc) - to proteins that affects how they behave.

In a study of adult mice, the researchers removed the gene that codes for OGT.

Removal of OGT leads to rise in fat and weight

Within 3 weeks of eliminating the gene from the primary nerve cells of the hippocampus and cortex, the mice experienced an increase in fat that doubled their weight.

A closer look at feeding patterns revealed that mice without OGT ate an average of 18 meals a day, the same as mice with OGT, but those without OGT spent longer eating their food and consumed more calories at each meal.

The weight gain halted when food intake was restricted to that of a normal lab diet.

Seeking an explanation, the researchers focused on the hypothalamus, known for its role in controlling body temperature, feeding, sleep and metabolism.

OGT was found to be missing from a small subset of nerve cells within a cluster of neurons called the paraventricular nucleus. Previous research has shown that these cells are involved in the signaling process relating to appetite and food intake.

Dr. Lagerlöf then looked for changes in the levels of specific factors that might be affected by the lack of OGT.

He found no impact on most of these factors and concluded that the reason for the weight gain did not lie with the better-known appetite signals.

Lack of OGT reduces effectiveness of synapses

The next step was to look at the chemical and biological activity of the cells with missing OGT.

The team measured the background electrical activity in brain cells that do not send signals, and they found three times fewer incoming synapses on the cells, compared with normal cells.

The scientists checked this by genetically manipulating the cells in the paraventricular nucleus, to enable them to add blue light-sensitive proteins to their membranes.

They then stimulated the cells with a beam of blue light, whereupon the cells emitted signals to other parts of the brain, and the daily food intake of the mice fell by 25%.

Huganir says:

"That result suggests that, in these cells, OGT helps maintain synapses. The number of synapses on these cells was so low that they probably aren't receiving enough input to fire. In turn, that suggests that these cells are responsible for sending the message to stop eating."

Finally, since glucose is needed to produce GlcNAc, the researchers looked at the impact of glucose levels on OGT activity. Glucose levels increase after meals.

When glucose was added to nerve cells in vitro, the proportion of proteins with GlcNAc increased in relation to the amount of glucose.

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